This project studies the neuroendocrine control of reproduction in animals and human subjects, with focus on a) the regulation of the ovulatory cycle and episodic gonadotropin secretion; b) photoperiodic control of seasonal reproduction; c) hypothalamic and lactational amenorrhea; d) premature ovarian failure; and e) luteal phase dysphoric disorder: (A) Ovulatory Cycle: The role of progesterone in the regulation of ovulation was studied in cycling women and in rats. In women, blockade of the preovulatory rise in progesterone consistently delayed ovulation, an effect reversed with progesterone administration, indicating an important role for progesterone in the timing of ovulation. In rats, mRNA's for hypothalamic CRH and pro-opiomelanocortin (POMC) showed marked variations around the time of the ovulatory gonadotropin surge, suggesting that in opiate peptides may also modulate the surge. POMC changes paralleled those of levels of progesterone. (B) Photoperiodism: Previous work has established that photoperiod strongly modulates reproductive function in rhesus monkeys. Pinealectomy abolishes these responses and leaves animals either acyclic or with free-running cycles. (C) Lactational Amenorrhea: Lactating amenorrheic women were treated with pulsatile gonadotropin-releasing hormone. This regimen restored cyclic ovarian function to a degree identical to that of control subjects, indicating that the interruption of the menstrual cycle during lactation is entirely central. Because opioids can underlie hypothalamic amenorrhea, CRH and POMC mRNA's were studied in lactating anestrus rats. Both peptide messages were markedly reduced. (D) Premature Ovarian Failure (POF): was studied in patients and in a mouse model of autoimmune ovarian disease. In contrast to normal menopause, many patients with POF were found to have follicles, which allows the possibility of remission. In the A/J mouse strain, neonatal thymectomy leads to failure of clonal deletion with autoimmune ovarian failure; however, other strains do not manifest disease after thymectomy, indicating alternative mechanisms of tolerance. (E) LLPDD: The linkage between symptoms and the luteal phase of the cycle was studied by truncating the luteal phase with a progesterone antagonist. Despite the hormonal changes, symptoms followed the same time course as in the control groups. This finding suggests a re-evaluation of the biology of LLPDD as an intrinsically periodic disorder for which the cycle serves as a Zeitgeber.